2-amino-3-aroyl-benzo[β]thiophenes and methods for preparing and using same to produce 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)-benzoyl]benzo[β]thiophenes

ABSTRACT

A group of 2-amino-3-aroyl-benzo[β]thiophenes are prepared by treating an aldehyde with an anion of dimethylamino thioformamide, cyclizing the α-hydroxy thioamide, and subsequently acylating the benzo[β]thiophene to yield the 2-amino-3-aryl derivative. These compounds may be treated with suitable phenyl Grignard reagents, and after deprotection, yield 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[.beta.]thiophene.

BACKGROUND OF THE INVENTION

This invention relates to the field of pharmaceutical chemistry, andprovides an advantageous process for preparing a group of6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[β]thiophenes.More specifically, the invention relates to methods for preparing novel2-amino-3-aroylbenzo[β]thiophenes and the subsequent conversion of thosethiophenes to the corresponding 2-(4-hydroxyphenyl) derivatives.

Ablenas et al., Can. J. Chem. 65: 1800-1803 (1987) teach the preparationof various 2-aryl-2-hydroxy thioacetamides and their subsequentcyclization to 2-aminobenzothiphenes[[benzo[β]thiophenes] with methanesulfonic acid (MeSO₃ H).

Chippendale et al., J.C.S. Perkin I, 1168-1172 (1976) disclose thepreparation of certain 2- and 3-(secondary amino)benzo[β]thiophenes andthe acylation of2-(secondary amino)benzothiophenes.

Most of the compounds prepared by the process of this invention aretaught in U.S. Pat. No. 4,133,814.

SUMMARY OF THE INVENTION

The present invention provides novel intermediates that unexpectedlyallow for the convenient synthesis of6-hydroxy-2-(4-hydroxyphenyl)-3-(4-hydroxybenzoyl)benzo[β]thiopheneshaving different functional groups on each of the three individualphenolic oxygens.

The invention also provides methods for preparing6-hydroxy-2-(4-hydroxyphenyl)-3-(4--hydroxybenzoyl)benzo[β]thiopheneshaving a variety of substituents on the phenolic oxygens. The inventivemethods also avoid the use of reagent materials that have beenidentified with waste treatment problems. For example, the inventivemethod can avoid the use of aluminum chloride in the acylation step.

Thus, the invention provides compounds of formula I ##STR1## where Rrepresents C₁ -C₆ alkyl, R" represents C₁ -C₆ alkyl amino C₁ -C₆ alkyl,or --(CH₂)_(n) N(R₁)(R₂) where n is an integer of 1 to 4, and R₁ and R₂are independently C₁ -C₁₀ alkyl, or R₁ and R₂ combine to form C₄ -C₆polymethylene or --(CH₂)2O(CH₂)₂ --; and R₃ and R₄ are independently C₁-C₆ alkyl or combine to form C₄ -C₆ polymethylene. Treatment of thecompounds of Formula I with phenyl Grignard reagents unexpectedlyaffords 2-phenyl-6-alkoxy-3-aroyl benzo[β]thiophenes.

The invention also provides a convenient process for preparing3-aroyl-2-phenyl benzo[β]thiophenes via2-amino-3-aroyl-benzo[β]thiophenes. This process comprises the steps of:

(a) condensing an aldehyde with a thioamide anion to produce aα-hydroxythioacetamide of the formula: ##STR2## (b) cyclizing theα-hydroxythioacetamide to form a 6-alkoxybenzothiophene;

(c) acylating the benzothiophene with an acylating agent of the formula:##STR3## R₅ is an active ester or a hydrogen to yield a2-amino-3-aroyl-benzo[β]thiophene; and

(d) reacting the 2-amino-3-aroyl-benzo[β]thiophene with a phenylGrignard reagent.

The invention further provides methods for preparing compounds offormula III ##STR4## where R₆ and R₇ are hydrogen; comprising preparing6-methoxy-(4-methoxyphenyl)-3-[4-(2-dialkylaminoethoxy)benzoyl]benzo[.beta.]thiophenesas described above and subsequently dealkylating the resultingbenzo[β]thiophenes with a sulfur compound.

DETAILED DESCRIPTION OF THE INVENTION

In this document, all temperatures will be stated in degrees Celsius.All amounts, ratios, concentrations, proportions and the like will bestated in weight units, unless otherwise stated, except for ratios ofsolvents which are in volume units.

In the formulas above the general terms bear their usual meanings. Forexample, the term C₁ -C₄ primary or secondary alkyl refers to groupssuch as methyl, ethyl, propyl, s-butyl, i-butyl and the like. The termC₁ -C₄ alkyl includes the above groups and also includes t-butyl. Theterm C₁ -C₄ alkoxy refers to straight or branched chain lower alkoxygroups such as methoxy, ethoxy, propoxy, isopropoxy, butyloxy and thelike. The term C₄ -C₆ polymethylene refers to tetramethylene,pentamethylene and hexamethylene. The term C₁ -C₆ alkyl includes the C₁-C₄ groups described above and various straight or branched chain pentyland hexyl groups.

The term "substituted phenyl" refers to a phenyl molecule having one ortwo substituents selected from the group consisting of C₁ -C₄ alkyl, C₁-C₅ alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro orfluoro)methyl. "C₁ -C₅ alkoxy" represents a C₁ -C₅ alkyl group attachedthrough a carbon bridge such as, for example, methoxy, ethoxy,n-propoxy, isopropoxy, and the like.

The following group of representative final products of the process andof this invention will be mentioned, to assure that the reader fullyunderstands the overall purpose of the process:

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-dimethylamino-ethoxy)benzoyl]benzo[.beta.]thiophene;

3-[4-(2-ethoxymethylaminoethoxy)benzoyl]-6-hydroxy-2-(4-hydroxylphenyl)benzo[β]thiophene;

3-[4-(2-ethoxylisopropylaminoethoxy)benzoyl]-6-hydroxy-2-(4-hydroxyphenyl)benzo[β]thiophene;

3-(4-(2-dibutylaminoethoxy)benzoyl]-5-hydroxy-2-(4-hydroxyphenyl)benzo[.beta.]thiophene;

3-[4-(2-(1-methylpropyl)methylaminoethoxy]-benzoyl]-6-hydroxy-2-(4-hydroxyphenyl)benzo[β]thiophene;

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-[2-di(2-methylpropyl)aminoethoxy]benzoyl]benzo[β]thiophene;

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinoethoxy)benzoyl]benzo[.beta.]thiophene;

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[β]thiophene;

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-morpholinoethoxy)benzoyl]benzo[β]thiophene;

3-[4-(2-hexamethyleneiminoethoxy)benzoyl]-6-hydroxy-2-(4-hydroxyphenyl)benzo[β]thiophene.

The final6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[β]thiophenecompounds are tissue specific estrogenic agonist/antagonists and, thus,are useful for estrogenic, antiestrogenic and antiandrogenic therapy.Accordingly, they are useful in treating pathological conditions ofendocrine target organs, which conditions are dependent or partiallydependent on an estrogen or on an androgen. Such conditions includemammary cancer, mammary fibrocystic disease, cancer of the prostate, andbenign prostatic hypertrophy.

U.S. Pat. No. 4,131,814 teaches that certain of the compounds are alsouseful as anti-cancer and anti-fertility drugs. The antiestrogenic andantiandrogenic efficacy of a preferred compound prepared by thisinvention,6-hydroxy-2-(4-hydroxyphenyl)-3-[4(2-piperidinoethoxy)benzoyl]benzo[β]thiophene,is explained in further detail in U.S. Pat. No. 4,413,068.

The dose of a compound to be administered to a human is rather widelyvariable. It should be noted that it may be necessary to adjust the doseof a compound when it is administered in the form of a salt, such as alaurate, the salt-forming moiety of which has an appreciable molecularweight. The general range of effective administration rates of thecompounds is from about 0.05 mg/kg/day to about 50 mg/kg/day. Apreferred rate range is from about 0.1 mg/kg/day to about 10 mg/kg/day,and the most highly preferred range is from about 0.1 mg/kg/day to about5 mg/kg/day. Of course, it is often practical to administer the dailydose of a compound in portions at various hours of the day.

The route of administration of the compounds is not critical. Thecompounds are known to be absorbed from the alimentary tract, and so itis usually preferred to administer a compound orally for reasons ofconvenience. However, the compounds may equally effectively beadministered percutaneously, or as suppositories for absorption by therectum, if desired in a given instance.

The compounds are usually administered as pharmaceutical compositions.All of the usual types of compositions may be used including tablets,chewable tablets, capsules, solutions, parenteral solutions, troches,suppositories and suspensions. Compositions are formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or a convenient volume of aliquid. In general, compositions contain from about 0.000006% to about60% of compound, depending on the desired dose and the type ofcomposition to be used.

The activity of the compounds does not depend on the composition inwhich it is administered or on the concentration of the composition.Thus, the compositions are chosen and formulated solely for convenienceand economy.

The preferred compounds of formula I include those where R₄ is methyl,R' is a N,N-dialkyl amino ethyl group and R₃ and R₄ are methyl. Aparticularly preferred compound of Formula I is2-N,N-dimethylamino-6-methoxy-3-[4-(2-piperidinoethoxy)benzoyl]benzo[.beta.]thiophene.This compound is particularly useful in a process for convenientlypreparing the final 2-hydroxyphenyl benzo[β]thiophenes.

The process of the inventions, leading to the2-amino-3-aroylbenzo[β]thiophene intermediates of Formula I and the thefinal compounds,6-hydroxy-2-(4-hydroxyphenyl)-3-(4-hydroxybenzoyl)benzo[β]thiophenes, isshown in Scheme I. ##STR5##

In Scheme I, R and R' independently represent C₁ -C₆ alkyl, and R"represents a variety of alkyl or aminoalkyl groups. The various R, R',and R" groups that may be included in the compounds and methods of theinvention will be evident in view of the following description of theprocess. In preferred processes, R" represents a 2-aminoethyl group, andmore preferably, a 2-piperidinoethyl group. As is discussed more fullybelow, the 2-aminoethyl group may be present in the acylating agentduring acylation. Optionally, the acylating agent may contain aprecursor of the 2-aminoethyl group.

2-AMINOBENZO[β]THIOPHENE FORMATION

The synthesis of the 2-aminobenzo[β]thiophene proceeds through thecondensation of a suitable aldehyde, such as, for example, anisaldehyde,with the anion generated from an N,N-dialkylthioformamide bydeprotonation with a suitable based, preferably an amide base such aslithium diisopropylamide in tetrahydrofuran at temperatures lower than-60° C., and preferably at about -78° C. In preferred embodiments (seeScheme II), the thioamide anion is trapped with trimethylsilyl chloride.The resulting trimethylsilyl thioacetamide, after optional isolation, isreacted with the aldehyde to yield an α-phenyl-α-hydroxythioacetamide (a2-phenyl-2-hydroxythioacetamide). The reaction of the silylatedthioamide is conducted with a catalyst such as sodium methoxide,titanium tetrachloride or tetrabutyl ammonium fluoride. The preferredcatalyst is tetrabutyl ammonium fluoride. ##STR6##

After isolation, the α-hydroxythioacetamide is treated with a strongacid, such as, for example, methanesulfonic acid, in a solvent to effectring closure. Suitable solvents for the ring closure include methylenechloride. When the aldehyde is a p-alkoxybenzaldehyde such asanisaldehyde, the sole product isolated is a 2-dimethylamino,6-alkoxybenzo[β]thiophene.

The 2-dimethylaminobenzothiophene is then reacted with a suitable acidchloride to provide a 2-amino-3-aroylbenzo[β]thiophene.

ACYLATION

Acylation of the 2-aminobenzothiophene can be done with an acylatingagent already containing the 2-aminoethyl (R ) group, yielding forexample, the 2-piperidinoethoxy group of the desired product.Alternatively, acylation of the 2-aminobenzothiophene can be done withan acylating agent having a precursor of the 2-aminoethyl group. Such aprecursor could be a group of the formula --(CH₂)_(n) X, wherein is 0, 1or 2 and X is a leaving group such as chlorine or bromine. The acylatingagents are discussed in detail below.

It has been surprisingly discovered that acylation according to theinvention may conveniently be carried out without using an acidscavenger such as carbonate or a tertiary amine. In fact, the additionof conventional tertiary amine acid scavengers can hinder or eventerminate the reaction.

It has further been discovered that when (a) the R" group of theacylating agent is --(CH₂)_(n) NR₁ R₂, (b) the reaction is conducted inthe presence of a protic acid such as hydrochloric acid, and (c) the R₅group of the acylating agent is chloro, bromo or iodo, the acylationreaction is selfcatalyzing. Without being bound by a particular theory,it is presently believed that the halogen, generated during acylationregenerates the protic acid. Preferably, the acylation is conductedwithout the use of a traditional Friedel-Crafts catalyst. Since thereaction is self-catalyzing, no catalyst need be added. Nevertheless, aprotic acid or an amino containing acylating agent complexed as a saltsuch as a hydrochloride salt may be added to effect acylation.

Accordingly, the acylation is essentially a modified Friedel-Craftsacylation, and may otherwise be carried out in the usual way.Optionally, either a Lewis acid or a proton acid may be used as aFriedel-Crafts catalyst; an excellent discussion of such catalystsappears in Olah, Friedel-Crafts and Related Reactions, IntersciencePubl., New York, London and Sidney, 1963, Vol. I Ch. III and IV.

As explained by Olah, the classical Friedel-Crafts catalysts were Lewisacids. Such metal halides as aluminum chloride, aluminum bromide, andchloride, boron trifluoride, boron trichloride, boron tribromide,titanium tetrachloride, titanium tetrabromide, stannic chloride, stannicbromide, bismuth trichloride and ferric chloride are well knowncatalysts and are useful in this acylation.

The proton acid catalysts useful for this acylation include suchsubstances as phosphoric acid, polyphosphoric acid, perchloric acid,chlorosulfonic acid, alkylsulfonic acids such as methanesulfonic andethanesulfonic acids toluenesulfonic and benzenesulfonic acids, sulfuricacid, chloroacetic acid and trifluoroacetic acid.

The acylation is ordinarily carried out in a solvent, and any inertorganic solvent which is not significantly attacked by the conditionsmay be used. For example, halogenated solvents such as dichloromethane,1,2-dichloromethane, chloroform and the like may be used, as canaromatics such as benzene, chlorobenzene and the like, alkanes such aspetroleum ether, hexane and the like, and nitrohydrocarbons such asnitrobenzene and nitroalkanes.

Unlike traditional Friedel-Crafts acylation, acylation according to anembodiment of the invention can be carried out in the presence oftoluene. Thus, it is not important to remove the toluene from materialsprepared in earlier steps of the process.

The acylations may be carried out at temperatures from about the ambienttemperature to about 100° preferably at the reflux temperature of thereaction mixture for processes catalyzed by the preferred proton acidcatalyst, trifluoromethanesulfonic acid, and preferably at about ambienttemperature for Lewis acid catalyzed processes.

The acylating agent is an active form of the appropriate benzoic acid,wherein R₅ is one of the recognized "active groups", such as chlorineatom, a bromine atom, or an activating ester. Appropriate activatingesters are formed with hydroxybenzotriazole, acylimidazoles,nitrophenols, pentachlorophenol, N-hydroxysuccinimide,dicyclohexylcarbodiimide and the like. The group R⁵ may also indicate ananhydride, especially a mixed anhydride such as those formed with smallcarboxylic acids such as acetic acid, formic acid and especiallysulfonic acids.

The preferred acylating agents are these wherein R₅ is chloro or bromo.Thus, the most highly preferred individual acylating agents are4-(2-piperidinoethoxy)benzoyl chloride, 4-(2-pyrrolidinoethoxy)benzoylbromide, 4-(2-pyrrolidinoethoxy)benzoyl chloride,4-(2-pyrrolidinoethoxy)benzoyl bromide,4-[2-(3-methylpyrrolidino)ethoxy]benzoyl chloride and4-[2-(3-methylpyrrolidino)ethoxy]benzoyl bromide.

It is preferred to carry out the acylation steps in an inert halogenatedsolvent such as chloroform, dichloromethane, chlorobenzene,1,2-dichloroethane and the like. In general, see as to such acylationreactions an article by Effenberger, Angew. Chem. Int. Ed. Engl. 19:151-230 especially 163-165 (1980).

DISPLACEMENT

When the starting compound is acylated with an aroyl compound containingan aminoethoxy precursor, the amino group of the product is subsequentlyput in place by displacing the X group with the appropriate secondaryamine. The X groups are leaving groups, preferably chloro or bromo,which are easily displaced by an amine according to known methods.

For example, the displacement is carried out in an inert solvent such asketones in the nature of acetone or methyl ethyl ketone, esters such asethyl acetate and propyl formate, alcohols such as methanol or ethanol,nitriles such as acetonitrile, or amides such as dimethylacetamide anddimethylformamide, or in such inert solvents as hexamethylphosphoramide,and in the presence of an acid scavenger such as alkali metal carbonatesand bicarbonates and the like. At least an equimolar quality of acidscavenger is needed, and preferably a moderate excess. The displacementis carried out at ambient temperature, or may be carried out atmoderately elevated temperatures from about ambient temperature to thereflux temperature of the reaction mixture.

More preferably, the displacement may be carried out in the additionalpresence of a catalytic amount of iodide ion, which acts as a catalystfor the displacement. When iodide is used in the mixture, thetemperature range is lower, from about 0° to preferably, the ambienttemperature, although elevated temperatures are possible in someinstances.

Further, the anion of the amine may be formed before the reaction iscarried out, as by contact with a very strong base such as sodiumhydride or an alkyl-lithium compound. The use of an anion does nototherwise change the manner in which the displacement is carried out,except that an acid scavenger is not needed.

MICHAEL ADDITION TO 2-AMINO, 3-AROYLBENZOTHIOPHENE

Subsequent to acylation, the 2-amino, 3-aroylbenzothiophene is reactedwith an appropriate Grignard reagent in a suitable solvent at atemperature of from about -78° C. to 20° C. In certain embodiments, theGrignard reagent may be reacted with the aminobenzothiophene in arefluxing solvent. Suitable solvents include ethyl ether andtetrahydrofuran. In a preferred embodiment, the Grignard reagent isgenerated from 4-bromoanisole and subsequently condensed with the2-amino, 3-aroylbenzothiophene in tetrahydrofuran at 0° C. to provideexclusively a 2-aryl-3-aroylbenzothiophene which comprises the basiccarbon-framework of the desired final compounds. This reaction is aunique and unexpected 1,4-Michael addition of the Grignard reagent tothe substrate with concomitant elimination of the dimethylamino group.This reaction surprisingly provides the 2-aryl-3-aroylbenzothiopheneexclusively. In preferred embodiments, a stoichiometric amount of theGrignard reagent is employed to avoid product deterioration. None of theother possible products, i.e., compounds i-iv below, are observed.##STR7## DEPROTECTION OF 3-AROYL-ALKOXYBENZO[β]THIOPHENE

The dialkoxybenzo[β]thiophene may be deprotected to yield the desireddihydroxy final product by treating the 3-aroyl-dialkoxy material with asulfur compound chosen from the group consisting of methionine andcompounds of the formula

    X--S--Y

where in X is hydrogen or unbranched C₁ -C₄ alkyl, and Y is C₁ -C₄ alkylor phenyl.

The sulfur compounds are preferably ,the alkylthiols, such asmethanethiol, ethanethiol, the preferred agent, isopropanethiol,butanethiol and the like; dialkyl sulfides, such as diethyl sulfide,butyl s-butyl sulfide, ethyl propylsulfide, butyl isopropyl sulfide,dimethyl sulfide methyl ethyl sulfide and the like benzenethiol;methiomine and alkyl phenyl sulfides such as methyl phenyl sulfide,ethyl phenyl sulfide, butyl phenyl sulfide and the like.

It has been found that the demethylation goes best when a substantialexcess amount of the sulfur compound is used, in the range of from about4 to about 10 moles per mole of the starting benzothiophene. The processcan be carried out, although less efficiently, with a smaller amount ofthe sulfur compound in the range of about 2 or 3 moles per mole ofstarting compound, and to improve the yield by the addition of about 1to 3 moles of an alkali metal halide, such as sodium, potassium orlithium chloride, iodide or or bromide. (A similar effect of sodiumiodide is shown by Niwa et al., Tet. Let. 22: 4239-40 (1981)).

The demethylation reaction goes well at about ambient temperature, inthe range of from about 15° to about 30°, and such operation ispreferred. However, the demethylation step may be carried out attemperatures in the range of from about -30° to about 50 ° if it isdesired to do so. Short reaction times in the range of about 1 hour havebeen found to be adequate.

In a preferred embodiment of the invention, the alkoxy protected2-aryl-3-aroylbenzothiophene is diprotected by reacting the protectedmaterial with n-propanethiol and aluminum chloride in a halogenatedsolvent such as chlorobenzene.

After the product has been demethylated, it is recovered and isolated byconventional means. Simple variations in the isolation can provide thedesired product as either the free amino compound or the hydrochloridesalt of the amine.

All of the above reaction steps give acceptable yields when thestoichiometric amounts of the reactants are used except as noted incertain specific steps above. As is normally the case in organicchemistry, improved yields are given by the use of an excess amount ofone of the reactants, and it is practical to use an excess amount of thecheaper or the more easily obtained reactant. For examples, in theformation of the protected starting compounds, it is practical andeconomical to use an excess of the acylating or sulfonating agent toassure complete reaction of the more expensive dihydroxy startingcompound. Excesses in the range of from about 1% to about 25% areconveniently used, when an excess of one reactant is desired.

The compounds may form acid addition salts. The salts are convenientlyformed, as is usual inorganic chemistry, by reacting the compoundprepared according to this invention with a suitable acid. The salts arequickly formed in high yields at moderate temperatures, and often areprepared by merely isolating the compound from a suitable acidic wash asthe final step of the synthesis. For example, salts may be formed withinorganic or organic acids

Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,and the like. Salts derived from organic acids, such as aliphatic monoand dicarboxylic acids, phenyl substituted alkanoic acids,hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids, may also be used. Such pharmaceuticallyacceptable salts thus include acetate, phenylacetate, trifluoroacetate,acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,α-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. A preferred salt is thehydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound with an equimolar or excess amount of acid. Thereactants are generally combined in a mutual solvent such as diethylether or benzene. The salt normally precipitates out of solution withinabout one hour to 10 days and can be isolated by filtration or thesolvent can be stripped off by conventional means.

All documents e.g., patents and journal articles, cited above or beloware hereby incorporated by reference in their entirety.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. Many of the products wereidentified by nuclear magnetic resonance (NMR) analysis. Such analyseswere run at 300 mHz in deuterochloroform unless stated otherwise.

EXAMPLE 1 Preparation ofα-hydroxy-α-(4-methoxyphenyl)N,N-dimethylthioacetamide

A sample of diisopropylamine (5.66 ml, 40.4 mmol) was dissolved in 27 mlof THF. The solution mixture was then chilled to 0° C. in an ice bathfollowed by addition of n-BuLi (24.9 ml 40.4 mmol, 1.62M in hexanes).After 15 min. of additional mixing, the solution mixture was chilled to-78° C. in an acetone/dry-ice bath followed by addition of a 10 ml THFsolution of a mixture of anisaldehyde (5.00 g, 36.7 mmol) andN,N-dimethylthioformamide (3.60 g, 40.4 mmol). A translucent-yellow,heterogeneous-looking mixture forms which is maintained at -78° C. for2.5 h followed by warming to 0° C. in an ice bath. The reaction mixturewas then treated with 20 ml of aqueous saturated ammonium chloride, thendiluted with 40 ml of ethyl ether, and the layers separated. The aqueouslayer was extracted with 20 ml of ethyl ether. The organic phases werecombined, dried over NaCl/MgSO₄, filtered, and then concentrated underreduced pressure to yield a solid/oil mixture (8.87 g). This mixture wasthen slurried with 10 ml of ethyl ether, and then chilled to 0° C. in anice bath. The mixture was then suction-filtered cold followed by washingof the filter cake with ice-cold ethyl ether (2×5 ml). The wet solid wasthen further dried under house vacuum to yield an off-white powder (3.90g). An additional crop of crystals were obtained from the combinedmother liquor and ethereal washings (0.84 g). The total yield was 57%.

(Analytical purity was achieved by recrystallization from ethanol, mp101° C.)

Analysis for C₁₁ H₁₅ NO₂ S Calc.: C, 58.64; H, 6.71; N, 6.22 Found: C,58.85; H, 6.80; N, 6.13

EXAMPLE 2 Preparation of 2-N,N-dimethylamino-6-methoxy benzo[β]thiophene

A sample of the α-hydroxythioamide prepared in Example 1 (40.0 g, 177mmol) was dissolved in 1480 ml of methylene chloride. Methanesulfonicacid (57.0 ml, 888 mmol) was then added slowly with vigorous stirring(the reaction temperature was from 18.9° to 24.6° C.). The reaction wasthen allowed to proceed for 2 hours and (the reaction end point) wasconfirmed by TLC analysis 40% ethyl acetate/hexanes, SiO₂). The reactionmixture (deep red solution) was then treated with 300 ml of aqueoussaturated sodium carbonate followed by 100 ml of water with vigorousstirring. The layers were separated and the organic phase dried withsolid sodium chloride (˜5 g), decanted, and then concentrated underreduced pressure to yield a solid (51.0 g). This solid was thenrecrystallized from 200 ml of ethanol which yielded a yellow solid whichwas dried at 50° C. overnight under house vacuum. Obtained coarse yellowpowder (29.2 g, 79%)

(Analytically pure sample has mp: 75°-76° C.)

Analysis for C₁₁ H₁₃ NOS Calc.: C, 63.74; H, 6.32; N, 6.76 Found: C,63.49; H, 6.32; N, 6.74

EXAMPLE 3 Preparation of2-N,N-dimethylamino-6-methoxy-3-[4-(2piperidinoethoxy)benzoyl]benzo[β]thiophene

A sample of the 2-dimethylaminobenzothiophene prepared in Example 2(10.3 g, 49.8 mmol) and 4-(2-piperidinoethoxy)benzoyl chloridehydrochloride (15.9 g, 52.3 mmol) were partially dissolved in 100 ml ofchlorobenzene. The mixture was warmed in a 100°-105° C. oil bath for 9h. The mixture was then allowed to cool to room temperature over onehour. (Complete solidification of the mixture occurred on cooling).

The solidified mixture was then broken up and treated with aqueoussaturated sodium carbonate (60 ml), followed by water (30 ml), thenmethylene chloride, then 50% aqueous sodium hydroxide (10 ml). Afterstirring for a short period, the mixture was diluted with 300 ml ofmethylene chloride and 100 ml of water. The layers were separated andthe organic layer washed with 50% saturated sodium carbonate (40 ml).The layers were separated and the organic phase dried over solid sodiumchloride (5 g), then decanted, and concentrated under reduced pressureto yield a thick dark oil (24.6 g). Purification was achieved by elutionthrough an SiO₂ column (29×5 cm) with methylene chloride (1000 ml)followed by 5% methanol/methylene chloride (3000 ml). The fractionscontaining the desired product were collected and concentrated to yielda thick dark oil (19.8 g, 91% weight yield, 84% pure by H-NMR). Corr.yield=76%.

(Analytical purity could be achieved by recrystallization fromacetonitrile, mp 209°-211° C. (decomp.))

Analysis for C₂₅ H₃₀ N₂ O₃ S Calc.: C, 68.46; H, 6.89; N, 6.39; S, 7.31Found: C, 68.19; H, 6.98; N, 6.32; S, 7.35

EXAMPLE 4 Preparation of2-N,N-dimethylamino-6methoxy-3-[4-(2-piperidinoethoxy)benzoyl]benzo[β]thiophenehydrochloride

A sample of the 2-dimethylaminobenzothiophene prepared in Example 2 (104mg, 0.50 mmol) and 4-(2-piperidinoethoxy)benzoyl chloride hydrochloride(152 mg, 0.50 mmol) were partially dissolved in 100 ml of toluene. Themixture was heated to reflux in a 120° C. oil bath for 16 h. The mixturewas then allowed to cool to room temperature, and then filtered. Thefilter cake was allowed to air dry yielding a bright yellow powder (235mg, 99% weight yield, 74% pure by HPLC). Corr yield ca. 74%.

Analysis for C₂₅ H₃₁ ClN₂ O₃ S. Calc.: C, 63.21; H, 6.58; N, 5.90; S,6.75; Cl, 7.46 Found: C, 63.09; H, 6.54; N, 5.76; S, 7.05; Cl, 7.61

EXAMPLE 5 Preparation of2-(4-methoxyphenyl)-6-methoxy-3-[4-(2-piperidinoethoxy)benzoyl]benzo[.beta.]thiophenehydrochloride

A sample of the 3-aroyl, 2-aminobenzothiophene prepared in Example 3,(252 mg, 0.575 mmol) was dissolved in 5 ml of THF in a dry 25 ml rbfequipped with a magnetic stir bar and septum under a dry nitrogenatmosphere. The solution mixture was chilled to 0° C. in an ice bathfollowed by the addition of as solution of 4-methoxyphenyl magnesiumbromide (1.41 ml, 2.51 mmol, 1.78M in THF). After 10 minutes, thereaction mixture was treated with 10 ml of water then diluted with 20 mlof methylene chloride. The emulsion that forms was allowed to separateand the organic phase then separated, dried over MgSO₄, filter andconcentrated to yield a yellow oil (384 mg). This crude mixture was thenpurified by silica column chromatography (methylene chloride-5%methanol/methylene chloride gradient). Obtained a light yellow oil (260mg, 90% yield).

EXAMPLE 6 Preparation of2-(4-methoxyphenyl)-6-methoxy-3-[4-(2-piperidinoethoxy)benzoyl]benzo[.beta.]thiophenehydrochloride

A sample of the 3-aroyl, 2-aminobenzothiophene (1.40 g. 3.19 mmol)prepared in Example 3 was dissolved in 15 ml of chlorobenzene in a dry50 ml rbf equipped with a magnetic stir bar and septum under a drynitrogen atmosphere. The solution mixture was chilled to 0° C. in an icebath followed by the addition of a solution of 4-methoxyphenyl magnesiumbromide (2.4 ml, 4.27 mmol, 1.78M in THF). The reaction was allowed toproceed with slow warming to room temperature over 1 hour. The reactionmixture was then chilled to 0° C. and then treated with 30 ml of HClsaturated methanol. The dark mixture was then partially concentratedunder reduced pressure to remove the methanol and excess HCl. A lightcolored solid precipitates on standing and the mixture then filteredcold (0° C.) to yield a pale yellow solid (1.39 g, 88% weight yield, 85%pure by HPLC). Corr. yield=75%.

Material was correlated to authentic material via HPLC analysis.

EXAMPLE 7 Preparation of6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo].beta.]thiophenehydrochloride

A sample of the benzothiophene prepared in Example 6 (0.70 g, 1.3 mmol)was suspended in 10 ml of chlorobenzene. To this mixture was addedaluminum trichloride (1.06 g, 8.0 mmol) in one part followed by additionof n-propanethiol (0.3 ml). The dark red mixture was then heated at 35°C. for 2.5 h. The reaction mixture was cooled in an ice bath (0° C.)followed by slow addition of 15 ml of THF. After 10 minutes ofadditional mixing, 10 ml of 6N aqueous HCl was added resulting in theformation of a precipitate. Stirring was continued over night. Themixture was filtered and filter cake allowed to air dry overnightyielding 0.63 g of a yellowish white solid, 95% yield.

Material was correlated to authentic material via HPLC analysis.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula: ##STR8## orpharmaceutically acceptable salts thereof; wherein R represents C₁ -C₆alkyl;R" represents C₁ -C₆ alkyl or --(CH₂)_(n) N(R₁)(R₂) where n is aninteger of 1 to 4, and R₁ and R₂ are independently C₁ -C₆ alkyl, or R₁and R₂ combine to form C₄ -C₆ polymethylene or --(CH₂)₂ O(CH₂)₂ --; andR₃ and R₄ are independently C₁ -C₆ alkyl or combine to form C₄ -C₆polymethylene.
 2. A compound according to claim 1, wherein R representsmethyl.
 3. A compound according to claim 1, wherein R" is --(CH₂)_(n)NR₁ R₂ and n is
 2. 4. A compound according to claim 1, wherein R₃ and R₄are methyl.
 5. A compound according to claim 3, wherein R₁ and R₂together represent pentamethylene.
 6. A compound according to claim 5,wherein R₃ and R₄ are methyl.
 7. A compound according to claim 1, whichis6-methoxy-2-dimethylamino-3-[4-(2-piperidinoethoxy)benzoyl]benzo[β]thiophene.